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Mol Ther ; 17(3): 455-62, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19107116

ABSTRACT

Our objective was to study the expression and function of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum protein recently identified as the calcium sensor that regulated Ca(2+)-released activated channels in T cells. STIM1 was found to be upregulated in serum-induced proliferating human coronary artery smooth muscle cells (hCASMCs) as well as in the neointima of injured rat carotid arteries. Growth factors-induced proliferation was significantly lower in hCASMC transfected with STIM1 siRNA than in those transfected with scrambled siRNA (increase relative to 0.1% S: 116 +/- 12% and 184 +/- 16%, respectively, P < 0.01). To assess the role of STIM1 in preventing vascular smooth muscle cells (VSMCs) proliferation in vivo, we infected balloon-injured rat carotid arteries with an adenoviral vector expressing a short hairpin (sh) RNA against rat STIM1 mRNA (Ad-shSTIM1). Intima/media ratios reflecting the degree of restenosis were significantly lower in Ad-shSTIM1- infected arteries than in Ad-shLuciferase-infected arteries (0.34 +/- 0.02 vs. 0.92 +/- 0.11, P < 0.006). Finally, we demonstrated that silencing STIM1 prevents activation of the transcription factor NFAT (nuclear factor of activated T cell). In conclusion, STIM1 appears as a major regulator of in vitro and in vivo VSMC proliferation, representing a novel and original pharmacological target for prominent vascular proliferative diseases.


Subject(s)
Membrane Glycoproteins/metabolism , Membrane Proteins/deficiency , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Neoplasm Proteins/deficiency , RNA, Small Interfering/genetics , Tunica Intima/cytology , Tunica Intima/metabolism , Active Transport, Cell Nucleus , Adenoviridae/genetics , Animals , Base Sequence , Cell Differentiation , Cell Proliferation , Cells, Cultured , Coronary Vessels/cytology , Coronary Vessels/injuries , Coronary Vessels/metabolism , Genetic Vectors/genetics , Humans , Male , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , NFATC Transcription Factors/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Rats , Rats, Wistar , Stromal Interaction Molecule 1 , TRPC Cation Channels/metabolism , Tissue Culture Techniques , Up-Regulation
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